Apolipoprotein J (clusterin, SGP-2) expression is increased during Alzheimer disease (AD) and to a lesser extent during normal brain again. New data shows that apoL can activate microglia in vivo and in vitro. We propose the hypothesis that apoJ expression is an adverse factor in AD and aging. In vitro, apoJ blocks the fibrillogenic pathway of AB aggregation and favors the formation of soluble toxic oligomers (ADDLs). New data show that ADDLs arise in AD brains. The effect of apoJ will be tested by infusion of apoJ into APP transgenic mice and in begenic apoJ-deficient x APP over-expressing mice. We will manipulate aging and AD-like changes in APP transgenics with caloric restriction and ibuprofen. We also predict that apoJ-deficiency will attenuate microglial activation during normal aging. In vitro studies with primary glial cultures from wildtype and apoJ-deficient mice will examine mechanisms of apoJ in microglial activation and in the sensitivity of neurons to AB.